title: Cell-cycle kinases coordinate the resolution of recombination intermediates with chromosome segregation.
abstract: Homologous recombination leads to the formation of DNA joint molecules (JMs) that must be resolved to allow chromosome segregation, but how resolution is temporally coupled with chromosome segregation is unknown. Here, we have analyzed the role of the cell-cycle kinases Cdk and Cdc5 in coordinating these events through their involvement in the phosphoregulation of the Mus81-Mms4 nuclease. By identifying CDC5 and MMS4 mutants that uncouple Mus81-Mms4 activation from cell-cycle progression, we show that JM disengagement, prior to anaphase initiation, safeguards chromosome segregation. By simultaneously stimulating the cleavage of cohesin and activating Mus81-Mms4 at the G2/M transition, Cdk and Cdc5 coordinate the sequential elimination of all chromosomal interactions in preparation for chromosome segregation. Conversely, untimely Cdc5 expression increases crossover frequency due to premature activation of Mus81-Mms4. Therefore, temporal restriction of JM resolution, imposed by Cdk/Cdc5, minimizes the potential for loss of heterozygosity while preventing chromosome missegregation and aneuploidy.
authors.affiliation: London Research Institute, Cancer Research UK, Clare Hall Laboratories, South Mimms, Herts EN6 3LD, UK.
authors.forename: Joao
authors.initials: J
authors.lastname: Matos
authors.forename: Miguel G
authors.initials: MG
authors.lastname: Blanco
authors.forename: Stephen C
authors.initials: SC
authors.lastname: West
mesh_terms: D000595:Amino Acid Sequence; D017489:CDC28 Protein Kinase, S cerevisiae / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D020090:Chromosome Segregation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism; D045585:Flap Endonucleases / Q000235:genetics / Q000378:metabolism; D059765:Homologous Recombination; D008969:Molecular Sequence Data; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000097722:Cohesins
chemical_list: D017489:CDC28 Protein Kinase, S cerevisiae; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D004720:Endonucleases; D045585:Flap Endonucleases; D017346:Protein Serine-Threonine Kinases; D029701:Saccharomyces cerevisiae Proteins; D000097722:Cohesins; C081927:CDC5 protein, S cerevisiae; C411624:MUS81 protein, S cerevisiae; C112337:MMS4 protein, S cerevisiae